The depressant barbiturates potentiate GABA-mediated inhibition in the central nervous system. The chronic administration of these barbiturates probably produces a prolonged, perhaps continuous potentiation of GABA-mediated pre- and postsynaptic inhibition. Thus it is the central hypothesis of this proposal that ensuing compensatory responses of the central nervous system to this prolonged potentiation of GABA-mediated inhibition are significant factors in the development of barbiturate tolerance and/or dependence. Gas chromatographic assays of GABA concentrations, pharmacological measures of GABA turnover, receptor assays for Na ion independent specific GABA binding and a recently developed retina model for studying barbiturate potentiation of GABA receptor mediated inhibition will be employed in the course of this project. These procedures will be used in experiments to determine if the mechanisms which are proposed (1) compensate for the prolonged potentiation of GABA and (2) are involved in the development of barbiturate tolerance and dependence. If the GABA system is shown to have a significant role in the development of barbiturate dependence, then specific pharmacologic agonists or antagonists of GABA may have an important future role in the clinical treatment of barbiturate abstinence syndrome.